title: Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine alpha-hydroxylating monooxygenase (PHM).
abstract: Peptidyl alpha-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of alpha-amidated peptide hormones in mammals and insects. PHM is a potential target for the development of inhibitors as drugs for the treatment of human disease and as insecticides for the management of insect pests. We show here that relatively simple ground state analogs of the PHM substrate hippuric acid (C(6)H(5)-CO-NH-CH(2)-COOH) inhibit the enzyme with K(i) values as low as 0.5microM. Substitution of sulfur atom(s) into the hippuric acid analog increases the affinity of PHM for the inhibitor. Replacement of the acetylglycine moiety, -CO-NH-CH(2)-COOH with an S-(thioacetyl)thioglycolic acid moiety, -CS-S-CH(2)-COOH, yields compounds with the highest PHM affinity. Both S-(2-phenylthioacetyl)thioglycolate and S-(4-ethylthiobenzoyl)thioglycolic acid inhibit the proliferation of cultured human prostate cancer cells at concentrations >100-fold excess of their respective K(i) values. Comparison of K(i) values between mammalian PHM and insect PHM shows differences in potency suggesting that a PHM-based insecticide with limited human toxicity can be developed.
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA. merkler@cas.usf.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Merkler
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Asser
authors.forename: Laura E
authors.initials: LE
authors.lastname: Baumgart
authors.forename: Natalie
authors.initials: N
authors.lastname: Carballo
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Carpenter
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Chew
authors.forename: Casey C
authors.initials: CC
authors.lastname: Cosner
authors.forename: Jodi
authors.initials: J
authors.lastname: Dusi
authors.forename: Lamar C
authors.initials: LC
authors.lastname: Galloway
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lowe
authors.forename: Edward W
authors.initials: EW
authors.lastname: Lowe
authors.forename: Lawrence
authors.initials: L
authors.lastname: King
authors.forename: Robert D
authors.initials: RD
authors.lastname: Kendig
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kline
authors.forename: Robert
authors.initials: R
authors.lastname: Malka
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Merkler
authors.forename: Neil R
authors.initials: NR
authors.lastname: McIntyre
authors.forename: Mindy
authors.initials: M
authors.lastname: Romero
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Wilcox
authors.forename: Terence C
authors.initials: TC
authors.lastname: Owen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006626:Hippurates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006626:Hippurates; D007306:Insecticides; D009097:Multienzyme Complexes; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase